Neal D. Shore, MD Atlantic Urology Clinic, LLC - PowerPoint Presentation

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Neal D. Shore, MDAtlantic Urology Clinic, LLCMyrtle Beach, SC

Other Side Effects: Perception vs. Evidence

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Common Adverse Effects of Androgen Deprivation Therapy

Hot flashes

Loss of libido/ED

Fatigue

AnemiaMuscle lossGynecomastia

Obesity/

Sarcopenia

Diabetes

Cardiovascular disease

Osteoporosis/fracture

Psychological: depression, memory difficulties, emotional liability

Slide3

Testosterone: Target Organs

brain

libido, mood, cognition

heart

cardiovascular health

liver

protein synthesis

kidney

stimulation of erythropoietin

production

male sexual organs

penile growth

spermatogenesis, erection

prostate growth and function

bone marrowstimulation of stem cells

skinhair growth, balding, sebum production

musclestrength, volume, energyreduction in visceral fat

bone

strength and density

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Androgen Deprivation Therapy

“Androgen Deprivation Syndrome”“Androgen Withdrawal Syndrome”

“LHRH Syndrome”

“Medical

Andropause”Constellation of symptoms and conditions

ADT now used more in non-metastatic prostate cancer, exposing men to ADT for longer periods

Concerns growing over ADT side effects

Arch Intern Med. 2006;166:465-471; Oncologist

. 2003;8:474-

487

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ADT Causes a Variety of Specific Adverse Effects

Central nervous system

Fatigue

Reproductive system

Decreased libido

Erectile dysfunction

Musculoskeletal system

Osteoporosis/fractures

Obesity

Sarcopenia

Endocrine

Vasomotor flushing

Lipid alterations

Insulin resistance

Hematologic systemAnemia

Slide6

ADT has been Associated with Metabolic Changes

Metabolic syndrome is a disorder of energy utilisation and storage, diagnosed by co-occurrence of any 3 of

:

Abdominal (central) obesity

Elevated blood pressure

Elevated fasting plasma glucose

High serum triglycerides

Low high-density (HDL) cholesterol levels

Metabolic syndrome increases the risk of developing CVD

ADT leads to:Insulin resistanceAccumulation of subcutaneous fat and decreased lean body massIncreased glucose levelsAbnormalities in lipid levels

Kelly DM, Jones TH. J Endocrinol 2013;217:R25-45

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Metabolic Syndrome and Metabolic Changes

Induced by ADT are

Different

Metabolic syndrome

Metabolic changes with ADT

Increased triglycerides

Increased triglycerides

Increased visceral fat

Increased

subcutaneous fatReduced HDL

Increased HDLHypertensionHypertensionIncreased fasting glucoseIncreased fasting glucoseDecreased adiponectinIncreased adiponectin

Increased C-reactive proteinNormal C-reactive protein

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Abdominal Obesity and Sarcopenia

During ADT

Eugonadal

young man

Saylor and Smith. J Urol. 2009;181:1998-2008

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GnRH Agonists Significantly Increase Serum Lipids in Men with CaP

Smith MR et al.

J

Clin

Endocrinol

Metab

. 2002;87:599-603.

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GnRH Agonists Decrease Insulin Sensitivity in Nondiabetic Men with

PCa

Smith MR

et al

(2006) J

Clin

Endocrinol

Metab 91:1305-8

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ADT and Diabetes:Consistency Between Forms of ADT

Keating, O

’

Malley

, and Smith (2006) J

Clin

Oncol

24(27): 4448-56

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References: Keating et al (2006) JCO;

Alibhai

et al (2009) JCO; Keating et al (2010) JNCI

ADT and Diabetes:

Consistency Between Population-Based Studies

Hazard

Ratio

Confidence

Intervals

SEER-Medicare

(n= 73,196; 7055 events)1.44(1.34-1.55)Ontario registry(n= 39,418; 2573 events)1.24(1.11-1.21)Veterans Administration(n= 37,433, 4967 events)1.28

(1.19-1.38)

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Causal Association Between ADT

and Diabetes is Plausible

Smith MR

et al

(2002) JCEM 87:599-603

Smith MR

et al

(2006) JCEM 91:1305-8

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Practical Recommendations: Diabetes

Screening

Consider testing in all men treated with ADT at baseline and yearly thereafter while receiving ADT

Recommended test:

glycated

hemoglobin (HbA1c)

Prediabetes

=HbA1c 6.5-7.0%; diabetes=HbA1c >7%

Management of pre-diabetes

Treat other CHD risk factorsRepeat testing at least yearlyLifestyle interventions (with follow-up counseling):5–10% weight loss≥150 min/week of moderate physical activitySaylor PJ et al. J Gen Intern Med. 2009;24

Suppl 2:S389-S394.

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Other Recommendations based on RCT

Fatigue

Aerobic and resistance exercise

Gynecomastia

RT and tamoxifen both reduce

gynecomastia

compared with observation, but

tamoxifen

reduces it more

Sexual dysfunction- Intermittent ADT and Aerobic and resistance exerciseNguyen PL Eur Urol. 2014 Aug 2. [Epub ahead of print].

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Nead

et al. JCO 2016;34:566-571

Analyses based on 125 new diagnoses

of Alzheimer

’

s disease

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ADT and Alzheimer’s Disease

ADT Users and Non-ADT Users were dramatically different at baseline

Kevin T.

Nead

et al. JCO 2016;34:566-571

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ADT and Alzheimer’s Disease

Kevin T.

Nead

et al. JCO 2016;34:566-571

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Lack of specificity suggests NO causal link

between ADT and dementia

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Why Intermittent Androgen Deprivation?

Minimize adverse events

Maximize quality of life (QoL)

Delay development hormone resistant

prostate

cancer (HRPC)

Reduction of non-oncologic morbidity/mortality and cost of care

Tunn U. BJU

Int

2007;99 (

Suppl

1):19-22;

Boccon-Gibod

L et al. BJU Int 2007;100:738-43Gleave M et al Urol Oncol 2009,27:81-86

Androgen Deprivation Therapy (ADT) is associated withadverse events:Holzbeierlein JM Urol Clin NA 2006,33:181-90; Spry NA et al BJUI (2009)

Epub; Gomella, et al Urology. 2009 May;73:S28-35

Long-term: bone demineralization, anemia, muscle wasting, metabolic syndrome, depression development of hormone resistance

Intermittent Androgen Deprivation (IAD) therapy aims to:

Short

-term: hot flushes, loss of libido

, ED

, fatigue

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Conclusions

ADT causes

specific harms

Hot flashes, fatigue, anemia, sexual dysfunction,

sarcopenia, obesity, osteoporosis, and greater risks for fractures and diabetes

Not all harms associated with ADT are causal

Cardiovascular disease, dementia, colorectal cancer,

others

When considering harms linked ADT, consider strength, consistency, and biological plausibility of the association

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Thank you!